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Substances of Abuse and Hallucinogenic Activity: The Glutamatergic Pathway - Focus on Ketamine

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Abstract

This chapter analyzes the glutamatergic pathway involved in the induction of hallucinations. Indeed, the development of the so-called glutamate hypothesis of psychotic disorders arises from the evidence that glutamate signalling antagonism can induce psychotic symptoms in healthy subjects. Ketamine seems to have the capacity of inducing not only dissociative symptoms, but also psychotic symptoms such as hallucinations. The main molecular mechanism of action of ketamine is due to its glutamate-dependent property. Ketamine also has other glutamate-independent mechanisms of action which include interaction with dopaminergic receptors, as well as with opioid, muscarinic, serotonin, and noradrenaline ones. Ketamine primarily acts as a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, leading to an increase in glutamate release in prefrontal cortex. The antagonism on NMDA receptors is thought to cause the dissociative effect of the drug, engendering a disconnection between thalamus, neocortex, and limbic areas. Given that ketamine-induced symptoms resemble the positive and negative symptoms of schizophrenia, they represent a consistent and novel pharmacological model to understand the molecular basis of hallucinations.

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Acknowledgments

This chapter was supported by a grant from the AIFA (Proposal AIFA-2016-02364852).

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  1. Department of Neurosciences and Mental Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

    Gian Mario Mandolini, Matteo Lazzaretti, Alfredo Carlo Altamura & Paolo Brambilla

  2. Department of Psychiatry and Behavioural Neurosciences, University of Texas at Houston, Houston, TX, USA

    Paolo Brambilla

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    Paolo Brambilla

  2. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

    Massimo Carlo Mauri

  3. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

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Mandolini, G.M., Lazzaretti, M., Altamura, A.C., Brambilla, P. (2018). Substances of Abuse and Hallucinogenic Activity: The Glutamatergic Pathway - Focus on Ketamine. In: Brambilla, P., Mauri, M., Altamura, A. (eds) Hallucinations in Psychoses and Affective Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-75124-5_3

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